Role of phosphatidylinositol 3′-kinase/AKT pathway in diffuse large B-cell lymphoma survival

Uddin, Shahab; Hussain, Azhar R.; Siraj, Abdul K.; Manogaran, Pulicat; Al-Jomah, Naif A.; Moorji, Azadali; Atizado, Valerie; Al‐Dayel, Fouad; Belgaumi, Asim; El-Solh, Hassan; Ezzat, Adnan; Bavi, Prashant; Al‐Kuraya, Khawla S.

doi:10.1182/blood-2006-04-016907

Cited by 244 publications

(221 citation statements)

References 59 publications

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“…43 These data may implicate the PTEN/ phosphatidylinositol 3 0 -kinase (PI3K)/protein kinase B (AKT) pathway in the development and progression of DLBCL. 42,44 In addition, losses in region 17p13.1 also have been associated with the lack of a CR to escalated CHOP and a trend toward a short survival. These results are in agreement with previous studies, which associated inactivation of the TP53 gene with clinical progression, a poor prognosis, drug resistance, and low CR rates in patients with aggressive B-cell lymphoma.…”

Section: Discussionmentioning

confidence: 99%

Array comparative genomic hybridization identifies genetic regions associated with outcome in aggressive diffuse large B‐cell lymphomas

Robledo¹,

Garcı́a²,

Caballero³

et al. 2009

Cancer

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BACKGROUND: Diffuse large B‐cell lymphomas (DLBCLs) are the most common type of non‐Hodgkin lymphomas. With chemotherapy and progenitor stem cell transplantation, about 60% of patients with DLBCL are long‐term survivors. The International Prognostic Index identifies patients with different outcomes. However, biologic characteristics also may help to discriminate different treatments groups. METHODS: DNA copy number changes identified by array comparative genomic hybridization (array‐CGH) were studied in 40 patients who had DLBCL with a poor prognosis and who were treated uniformly with dose‐escalated cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and intensification before high‐dose chemotherapy with autologous stem cell transplantation. RESULTS: In total, 722 copy number changes were observed (median, 5 copy number changes per patient; range, 0‐75 copy number changes per patient), with a predominance of gains. Gains on 2p16 were present only in patients who failed to achieve a complete response after escalated CHOP therapy (P < .05). In univariate analysis, gains on 2p16 and losses on 17p13 (the tumor protein p53 gene TP53 gene) were associated with a poor response to the therapy. Furthermore, age >60 years and losses on 10q23.31 (the phosphatase and tensin homolog gene PTEN) or on 17p13 were associated with short survival. In multivariate analysis, only advanced age and losses on 10q23.31 retained an adverse prognostic impact. CONCLUSIONS: Array‐CGH identified multiple regions with common copy number changes, some of which were associated with outcome in patients with DLBCL. Cancer 2009. © 2009 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

Array comparative genomic hybridization identifies genetic regions associated with outcome in aggressive diffuse large B‐cell lymphomas

Robledo¹,

Garcı́a²,

Caballero³

et al. 2009

Cancer

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“…Endothelial cells in the neovascular capillaries and vessels consistently showed intense staining for PTEN (3 þ ) and acted as an internal positive control when present. p-AKT scoring was done as described earlier (Bose et al, 2006;Uddin et al, 2006). Briefly, p-AKT was scored as levels on an intensity scale ranging from 0 to 3.…”

Section: Microsatellite Markers and Analysesmentioning

confidence: 99%

Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population

Abubaker¹,

Bavi²,

Al-harbi³

et al. 2008

Oncogene

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Activation of the phosphatidylinositol 3 0 -kinase (PI3K)/ AKT pathway results in an increase in cell proliferation and survival. Somatic mutations within the PI3K catalytic subunit, PIK3CA are common cause of increasing PI3K activity and are believed to be oncogenic in many cancer types. Few reports addressed the association between PIK3CA mutations and tumor progression specifically in microsatellite instable (MSI) colorectal cancer (CRC). In the present study, we have evaluated PIK3CA mutational status in a series of 410 Middle Eastern CRC and 13 colon cell lines to study the prevalence of PIK3CA mutations in MSI cases, PTEN expression in CRC and possibility of therapeutic targeting of this set of patients. PIK3CA mutations were found in four of the cell lines tested and 51 colorectal carcinomas (12.2%). Three of these four mutated cell lines were MSI. PTEN was inactivated in 66.1% of the CRC. Furthermore, we observed a strong association between PIK3CA mutations and MSI status (P ¼ 0.0046) while PTEN loss was more frequent in microsatellite stable (MSS) CRC (P ¼ 0.043). A high prevalence of genetic alterations in PI3K/AKT pathway in Saudi cohort of CRC, predominance of PIK3CA mutations in the MSI subgroup and their possible involvement in development/progression of this subset of CRC are some of the significant findings of our study.

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“…29 DNA Laddering DNA-laddering assay was performed as previously described. 30 Briefly, cells (2 Â 10 6 ) were treated with and without indicated doses of PHA665752 for 24 h. The cells were harvested and resuspended in 200 ml 1 Â PBS. A total of 200 ml lysis buffer containing 6 mol/l guanidine HCL, 10 mmol/l urea, 10 mmol/l Tris-HCl, and 20% Triton X (v/v; PH 4.4) were added to the cells and incubated for 10 min at room temperature.…”

Section: Immunohistochemistrymentioning

confidence: 99%

HGF/c-Met pathway has a prominent role in mediating antiapoptotic signals through AKT in epithelial ovarian carcinoma

Uddin

Bavi

et al. 2011

Laboratory Investigation

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The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are overexpressed and/or activated in a variety of human malignancies. However, its role in epithelial ovarian carcinoma (EOC) has not been clearly elucidated. Therefore, we investigated the role of HGF/c-Met signaling pathway in a large series (156) of Saudi EOC patient samples, a panel of cell lines, and xenografts in a NUDE mouse model. Using immunohistochemistry, c-Met overexpression was found in 27.2% Middle Eastern EOC samples and was associated with an advanced tumor stage (P ¼ 0.0187). c-Met overexpression was also associated with antiapoptotic markers X-chromosome-linked inhibitors of apoptosis (XIAP) (P ¼ 0.0008) and Bcl-XL (P ¼ 0.0493) expression. Treatment of EOC cell lines with PHA665752 causes a dose-dependent inhibition of cell viability and induction of apoptosis. Furthermore, PHA665752 treatment causes dephosphorylation of AKT and downregulation of antiapoptotic proteins XIAP and Bcl-XL. In addition, PHA665752-induced apoptosis occurs through activation of Bax-mediated release of cytochrome c and activation of caspases. Finally, co-treatment of EOC with PHA665752 and cisplatin causes augmented effect on apoptosis of EOC cells and resulted in synergistic inhibition of EOC xenograft tumor growth in NUDE mice. These results indicate that c-Met/HGF pathway may be a potential target for therapeutic intervention for treatment of EOC.

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Role of phosphatidylinositol 3′-kinase/AKT pathway in diffuse large B-cell lymphoma survival

Cited by 244 publications

References 59 publications

Array comparative genomic hybridization identifies genetic regions associated with outcome in aggressive diffuse large B‐cell lymphomas

Array comparative genomic hybridization identifies genetic regions associated with outcome in aggressive diffuse large B‐cell lymphomas

Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population

HGF/c-Met pathway has a prominent role in mediating antiapoptotic signals through AKT in epithelial ovarian carcinoma

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